The impact of proliferating mast cells in the developing brain
增殖的肥大细胞对发育中的大脑的影响
基本信息
- 批准号:10630822
- 负责人:
- 金额:$ 4.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-11 至 2026-04-10
- 项目状态:未结题
- 来源:
- 关键词:AddressAdolescentAdultAffectAffectiveAgeAttentionB-LymphocytesBehaviorBioinformaticsBone MarrowBrainCell CountCell MaintenanceCell ProliferationCell ShapeCellsCentral Nervous SystemChildChildhoodChoroidChronicClinicalCommunicationComplexDataDevelopmentDevelopmental ProcessDiagnosisDiseaseEmbryoFosteringFoundationsFunctional disorderGrowth FactorHealthHelper-Inducer T-LymphocyteHeterogeneityHippocampusHistamineHomeostasisImmersionImmuneImmunologistInflammationInflammation MediatorsInflammatoryInnate Immune SystemInvadedLifeMediatorMentorshipMicrogliaMolecularMorphologyNeurodegenerative DisordersNeurodevelopmental DisorderNeurogliaNeuroimmuneNeurologic DeficitNeurologistNeuronsPathologyPatternPediatric NeurologyPerinatalPeripheralPhenotypePhysiciansPhysiologicalPhysiological ProcessesPopulationPositioning AttributeProcessProliferatingRattusRegulationResearchRoleSchizophreniaScientistShapesSignal TransductionSiteSkinSourceSpecificityStimulusSupporting CellTechniquesTestingThalamic structureTimeTissuesTrainingVascular Endothelial Growth Factorsautism spectrum disorderblood-brain barrier permeabilizationbrain cellbrain tissuecareercognitive functioncytokineexperimental studyglial cell developmentgranulocytehippocampal fissureimmune cell infiltrateimmunogenicinjuredinsightlateral ventriclemast cellmastocytosisneonatal brainnervous system disorderneuralneurodevelopmentneurogenesisneuron developmentnovelperinatal periodpostnatalrecruitresponsesingle-cell RNA sequencingstemsynaptogenesistraffickingtranscriptometranscriptomics
项目摘要
Project Summary
Both resident and peripheral immune cells are increasingly implicated in the pathophysiology of various
neurodevelopmental disorders, including autism, but the mechanisms by which these non-neuronal cells impact
the brain is largely unknown. Infiltrating immune cells in the brain readily respond to environmental triggers,
promoting persistent proinflammatory signaling that permanently alters developing cells and damages non-
renewing populations. The resident immune cells of the brain, microglia, regulate normal physiologic processes
to guide brain development, but little is known about the contribution of infiltrating immune cells to these same
processes. In my preliminary studies, I found thousands of mast cells, a component of the innate immune system,
inhabiting the lateral ventricles adjacent the hippocampus, throughout perinatal stages of brain development.
This raises the question – what role might such proinflammatory cells serve in the developing brain? Mast cells
(MC) are both highly sensitive to a variety of stimuli and reflexively produce a wide assortment of vasoactive
molecules, cytokines, and growth factors, making them a potential neuro-immune hub during neurodevelopment.
Moreover, since mast cells are so exquisitely responsive to inflammatory signals, they may serve dual functions:
potentially supporting cell genesis and maturation, or perpetrating damage. This proposal seeks to address gaps
in our understanding of MC recruitment, heterogeneity, and function in the developing brain to assess how this
population may contribute to neurodevelopmental disorders. We have shown, for the first time, that brain MC
are replicating along the hippocampal fissure and are maintained in this region for the first two postnatal weeks,
paralleling neurogenesis and microglial maturation occurring nearby. Advanced flow cytometric techniques will
test the hypothesis that they are locally proliferating, which MC do not typically do outside of the bone marrow
(Aim 1.1). To elucidate their functional and molecular identity in the developing CNS, we will perform single cell
RNA-sequencing of brain MCs and compare their transcriptome to prototypical MCs from the skin and bone
marrow (Aim 1.2). Findings from transcriptomic analyses will guide exploration of their mechanism of influence
on typical developmental processes in the hippocampus. Lastly, MC are well known to coordinate with microglia
in the injured adult brain, but this relationship has not been thoroughly explored during development. We will test
our hypothesis that MCs release signaling factors that promote microglial maturation in the hippocampus (Aim
2). These findings will reframe understanding of the developing brain as an immune-enabled site requiring
nuanced neuro-immune interactions to sustain developmental processes. This project fosters training in
bioinformatics and immersion in two historically independent fields to prepare me for a career investigating
neural-immune communication in health and disease. Scientific mentorship from neuroscientist Dr. Margaret
McCarthy and immunologist Dr. Nevil Singh, paralleled by clinical mentorship from neuroimmunologist Dr. David
Benavides, will establish a strong foundation for my life as a physician-scientist in the field of child neurology.
项目摘要
常驻免疫细胞和外周免疫细胞两者越来越多地涉及各种免疫缺陷的病理生理学。
神经发育障碍,包括自闭症,但这些非神经元细胞的影响机制,
大脑在很大程度上是未知的。大脑中浸润的免疫细胞很容易对环境触发做出反应,
促进持续的促炎信号传导,永久性地改变发育中的细胞并损害非炎症细胞。
更新人口。小胶质细胞是大脑中的常驻免疫细胞,它调节正常的生理过程
引导大脑发育,但很少有人知道浸润免疫细胞对这些相同的贡献。
流程.在我的初步研究中,我发现了数千个肥大细胞,先天免疫系统的一个组成部分,
在大脑发育的整个围产期阶段,栖息在海马附近的侧脑室。
这就提出了一个问题--这种促炎细胞在发育中的大脑中起什么作用?肥大细胞
(MC)对各种刺激高度敏感,并反射性地产生各种各样的血管活性物质,
分子、细胞因子和生长因子,使其成为神经发育过程中潜在的神经免疫枢纽。
此外,由于肥大细胞对炎症信号的反应如此灵敏,它们可能具有双重功能:
潜在地支持细胞发生和成熟或造成损害。该提案旨在弥补差距
在我们对发育中的大脑中MC募集、异质性和功能的理解中,
可能导致神经发育障碍。我们首次证明,大脑MC
沿着海马裂沿着复制,并在出生后的前两周内保持在该区域,
与附近发生的神经发生和小胶质细胞成熟平行。先进的流式细胞技术将
检验它们是局部增殖的假设,而MC通常不在骨髓外增殖
(Aim 1.1)。为了阐明它们在发育中的CNS中的功能和分子特性,我们将进行单细胞
脑MC的RNA测序并将其转录组与来自皮肤和骨骼的原型MC进行比较
骨髓(目标1.2)。转录组学分析的结果将指导其影响机制的探索
关于海马体中典型的发育过程。最后,众所周知,MC与小胶质细胞协调
在受伤的成年大脑中,这种关系在发育过程中尚未得到彻底的探索。我们将测试
我们的假设是MCs释放促进海马小胶质细胞成熟的信号因子(目的
2)。这些发现将重新理解发育中的大脑是一个免疫激活的部位,
微妙的神经免疫相互作用来维持发育过程。该项目促进以下方面的培训
生物信息学和沉浸在两个历史上独立的领域,为我的职业生涯做好准备,
健康和疾病中的神经免疫通讯。来自神经科学家玛格丽特博士的科学指导
麦卡锡和免疫学家内维尔·辛格博士,神经免疫学家大卫博士的临床指导
贝纳维德斯,将建立一个强大的基础,我的生活作为一个医生,科学家在儿童神经学领域。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Alexa Ciesinski Blanchard其他文献
Alexa Ciesinski Blanchard的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Alexa Ciesinski Blanchard', 18)}}的其他基金
The impact of proliferating mast cells in the developing brain
增殖的肥大细胞对发育中的大脑的影响
- 批准号:
10463954 - 财政年份:2022
- 资助金额:
$ 4.56万 - 项目类别:
相似海外基金
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 4.56万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The impact of changes in social determinants of health on adolescent and young adult mental health during the COVID-19 pandemic: A longitudinal study of the Asenze cohort in South Africa
COVID-19 大流行期间健康社会决定因素的变化对青少年和年轻人心理健康的影响:南非 Asenze 队列的纵向研究
- 批准号:
10755168 - 财政年份:2023
- 资助金额:
$ 4.56万 - 项目类别:
A Priority Setting Partnership to Establish a Patient, Caregiver, and Clinician-identified Research Agenda for Adolescent and Young Adult Cancer in Canada
建立优先合作伙伴关系,以建立患者、护理人员和临床医生确定的加拿大青少年和年轻人癌症研究议程
- 批准号:
480840 - 财政年份:2023
- 资助金额:
$ 4.56万 - 项目类别:
Miscellaneous Programs
Incidence and Time on Onset of Cardiovascular Risk Factors and Cardiovascular Disease in Adult Survivors of Adolescent and Young Adult Cancer and Association with Exercise
青少年和青年癌症成年幸存者心血管危险因素和心血管疾病的发病率和时间以及与运动的关系
- 批准号:
10678157 - 财政年份:2023
- 资助金额:
$ 4.56万 - 项目类别:
Fertility experiences among ethnically diverse adolescent and young adult cancer survivors: A population-based study
不同种族青少年和年轻成年癌症幸存者的生育经历:一项基于人群的研究
- 批准号:
10744412 - 财政年份:2023
- 资助金额:
$ 4.56万 - 项目类别:
Treatment development for refractory leukemia using childhood/adolescent, and young adult leukemia biobank
利用儿童/青少年和青年白血病生物库开发难治性白血病的治疗方法
- 批准号:
23K07305 - 财政年份:2023
- 资助金额:
$ 4.56万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Molecular design of Two-Way Player CAR-T cells to overcome disease/antigen heterogeneity of childhood, adolescent, and young adult cancers
双向 CAR-T 细胞的分子设计,以克服儿童、青少年和年轻成人癌症的疾病/抗原异质性
- 批准号:
23H02874 - 财政年份:2023
- 资助金额:
$ 4.56万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Effects of adolescent social isolation on adult decision making and corticostriatal circuitry
青少年社会隔离对成人决策和皮质纹状体回路的影响
- 批准号:
10756652 - 财政年份:2023
- 资助金额:
$ 4.56万 - 项目类别:
Adolescent trauma produces enduring disruptions in sleep architecture that lead to increased risk for adult mental illness
青少年创伤会对睡眠结构产生持久的破坏,从而导致成人精神疾病的风险增加
- 批准号:
10730872 - 财政年份:2023
- 资助金额:
$ 4.56万 - 项目类别:
Using Tailored mHealth Strategies to Promote Weight Management among Adolescent and Young Adult Cancer Survivors
使用量身定制的移动健康策略促进青少年和年轻癌症幸存者的体重管理
- 批准号:
10650648 - 财政年份:2023
- 资助金额:
$ 4.56万 - 项目类别: